Nearly every case of childhood fever is caused by one of two things: bacteria or viruses. However for a doctor, picking the right medication isn't always so straightforward, especially if a kid's only symptom is the fever. The U.S. Centers for Disease Control and Prevention (CDC) warns against prescribing antibiotics for bacterial infections in children when they are not needed, as this can contribute to drug resistance.

A new study reveals that the genetics of a feverish toddler can provide a simple answer. The findings could serve as a platform for new diagnostics that ultimately reduce the overprescription of antibiotics for children.

"It's a common problem that children develop a fever without any apparent cause," said senior author Dr. Gregory Storch, a professor of pediatrics at Washington University School of Medicine and whose team's research was published today. "Some of these kids have serious bacterial infections that can be life threatening, but the largest number have viral infections. The trouble is, from a practical standpoint, it's hard to know which is which."

The key to the new genetic test is white blood cells. These essential components of human immunity are charged with eliminating foreign invaders from the body. In the past, when doctors were facing a tricky diagnosis, they would take a small blood sample and count the number of white blood cells. The general rule was elevated white blood-cell counts were indicative of bacterial infections, while normal or low levels signaled a virus.

But this standard protocol was error-prone.

"We know there are many exceptions to that rule, and we certainly saw that in this study," said Storch. "A lot of patients with viral infections had elevated white-blood cell counts so doctors thought they had bacterial infections and prescribed antibiotics, which in fact were not necessary."

The Genes Within

Storch and his collegues took an alternative approach to capitalizing on white blood cells. Instead of merely counting the cells, his team explored how the genes inside of these cells responded to different infections.

They asked a simple question: which genes were turned on or turned off by bacteria or viruses during a fever? Using a special device called a microarray, the researchers analyzed 25,000 genes at once in blood samples collected from toddlers with fevers.

"The microarray basically tells us how a patient is reading the infection," said Storch.

The children were between two months to three years old, and for each case, the underlying cause — bacteria or virus — was already known.

The authors found that the genetic profiles of the white blood cells were drastic enough to group these children's illnesses in two different ways.

First, as hoped, feverish kids with bacterial infections could be distinguished from those with viral infections, Using these gene profiles, the doctors to accurately determine 90 percent of the time if a virus or bacteria was involved with a case. Standard tests are only correct 70 percent of the time, which argues that the genetic profile of white blood cells could assist clinical decision-making on how to best treat these fevers.

Their second discovery involved 'silent' infections. Bacteria and viruses don't always cause symptoms, and in a surprise twist, the researchers discovered major genetic variations in children with and without fever infected with identical germs. This finding suggests our bodies' immunity changes in the context of a fever, even when we're fighting the same pathogen.

"In the kids with a virus and a fever, many genes were very active, compared with kids who had viruses and no fever, whose genes were quiet," Storch explained. "The very active genes tell us that an infection is making a patient sick, while quiet genes tell us either there's no infection or maybe a bacterium or virus is there, but it's not causing fever or illness."

This is a subtle distinction that could improve standard testing, which sometimes can't tell if a virus is actually causing an illness or if it is a bystander to another germ.

In it's current form of analyzing 25,000 genes, this test would be too slow for use in doctor's office. Storch and his colleagues hope to isolate a subset of genes that could serve as simpler readout for these children with fevers in a follow-up study.

Source: Hu X, Yu J, Crosby SD, Storch GA. Gene expression profiles in febrile children with defined viral and bacterial infection. PNAS. 2013.